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WO1992004008A1 - Composition pour le traitement des douleurs oculaires - Google Patents

Composition pour le traitement des douleurs oculaires Download PDF

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Publication number
WO1992004008A1
WO1992004008A1 PCT/EP1991/001656 EP9101656W WO9204008A1 WO 1992004008 A1 WO1992004008 A1 WO 1992004008A1 EP 9101656 W EP9101656 W EP 9101656W WO 9204008 A1 WO9204008 A1 WO 9204008A1
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WO
WIPO (PCT)
Prior art keywords
pain
calcium channel
blocking agent
channel blocking
diltiazem
Prior art date
Application number
PCT/EP1991/001656
Other languages
English (en)
Inventor
Carlos Belmonte-Martinez
Roberto Gallego-Fernandez
Miguel Angel Pozo-Garcia
Juana Gallar-Martinez
Original Assignee
Universidad De Alicante
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universidad De Alicante filed Critical Universidad De Alicante
Priority to JP91513914A priority Critical patent/JPH05506035A/ja
Priority to AU83971/91A priority patent/AU644679B2/en
Priority to EP91915701A priority patent/EP0502143B1/fr
Priority to DE69114470T priority patent/DE69114470T2/de
Publication of WO1992004008A1 publication Critical patent/WO1992004008A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the topical application of calcium channel blocking agents for treating ocular pain and neurogenic inflammation and compositions useful for such application.
  • Pain is a well known phenomenon as an indicator of injury or tissue damage due to inflammation, ischemia, mechanical or other irritation [Juan, H., Prostaglandins as Mediators of Pain, Gen. Pharmacy. . 403-409 (1978)].
  • nociceptive primary afferents by intense thermal, mechanical or chemical stimuli.
  • activation involves chemical mediators that are released or synthesized in response to tissue damage [Fields, H. and Levine, J., Pain-Mechanisms and Management, Western Medical J. 141. 347-357 (1984)].
  • chemical mediators include lactic acid, hypertonic saline, histamine, 5- hydroxytryptamine, potassium chloride, acetylchoHne, purines, bradykinin and substance P which are referred to as algesic agents (Juan, H., Supra).
  • Prostaglandins and leukotrines can contribute to the activation of primary afferent nociceptors (Fields, H. and Levine, J., Supra).
  • Prostaglandins are uniquely distinguished from the other chemical mediators in that they induce a state of hyperalgesia by elevating the sensitivity of pain receptors to other painful or algesic stimuli.
  • the stimulation of primary afferents leads to action potentials in their axons which propagate to the spinal cord.
  • excited primary afferents release nuropeptides (substance P, calciotonin-gene-related peptide, neurokinin A) at their peripheral terminals.
  • Neuropeptides enhance inflammatory reactions in the injured tissue, contributing to vasodilation, edema, and increased vascular permeability; this phenomenon is called 'neurogenic inflammation'.
  • the nociceptors enter the gray matter of the superficial dorsal horn to synapse on nerve cells contributing to pain- transmission pathways such as the spinothalamic and spinoreticulothalamic tracts which terminate in two separate regions in the thalamus.
  • the two thalamic regions in turn project to different cortical sites (Fields, J. and Levina, J., Supra).
  • Anesthetics block neuronal transmission and affect sensation as well as pain.
  • Analgesics act by interfering with the activity of chemical mediators without affecting sensory input.
  • analgesics can be classified as falling into at least three loose groups: 1) the opiate-based (narcotic) analgesics; 2) the non-opiate analgesics; and 3) analgesics and antipyretics.
  • the opiate-based analgesics include opium derived alkaloids, including morphine, codeine, and their various derivatives, opiate antagonists, the several morphine derivatives which have morphine antagonist activity, but have analgesic activity.
  • n_,n-opiate analgesics Since these narcotic type drugs are addictive, a number of non- addictive, n_,n-opiate analgesics have been developed in an attempt to produce an analgesic which is highly efficient but not addictive.
  • analgesics and antipyretics are the salicylates and acetamide-containing compounds and the so-called non- steroidal anti-inflammatory drugs. They are non-addictive pain killers. As to their mode of action, drugs that block perception of pain may be said to act either centrally (such as narcotics) or peripherally.
  • Centrally acting narcotic drugs are true analgesics because they can relieve pain regardless of the etiology.
  • NSAIAs non-steroidal anti-inflammatory agents
  • PGE2 prostaglandin E2
  • Inhibitors of prostaglandin synthesis act avoiding the sensitizing effects of prostaglandins on nociceptive endings and therefore, the decrease in pain threshold.
  • NSAIAs Ophthalmic applications of various NSAIAs are also known, including the utilization of their anti-inflammatory properties for control of various ocular inflammations.
  • NSAIAs have been used for the treatment of non-inflammatory, localized pain, such as non-inflammatory ocular pain.
  • Calcium channel blockers or antagonists are compounds which delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemic conditions. Calcium overload, during ischaemia, can have a number of additional adverse effects which would further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly, promotion of cell necrosis.
  • the compounds are useful in the treatment or prevention of cardiac conditions, such as angina pectoris, cardiac arrhythmias, heart attacks and cardiac hypertrophy.
  • the compounds also possess vasodilator activity and are thus useful as antihypertensives and for the treatment of coronary vasospasm.
  • Calcium channel blockers of the verapamil type are known to lower elevated intraocular pressure. See U.S. Patent No. 4,981,871. Calcium channel blockers are not suggested as useful for treating pain, including ocular pain.
  • the present invention is based on the unexpected finding that compounds having calcium channel blocking activity efficiently relieve ocular pain, including ocular pain and inflammation associated with corneal injuries.
  • a topical composition, including a calcium channel blocking agent for the relief of eye pain offers several benefits over the use of systemic agents because of the decreased systemic absorption, which may decrease side-effects, and increased ocular absorption that can increase efficacy.
  • certain calcium channel blockers alleviate ocular pain associated with chemical stimuli but do not affect mechanical stimuli.
  • sustained discharges in nociceptive fibers are maintained by chemical mediators released by injured tissues, this invention permits the attenuation of pain elicited by these mediators without interfering with sensitivity to mechanical stimuli.
  • decrease of responsiveness of nociceptive terminals by calcium channel blockers reduce neurogenic inflammation resulting in the release of neuropeptides by excited nociceptors.
  • the present invention relates to a method for treating ocular pain in a mammal afflicted by such pain, which method comprises applying to the eye of said mammal an effective amount of a calcium channel blocking agent in a pharmaceutically acceptable vehicle.
  • the present invention relates to the use of calcium channel blocking agents for the treatment of ocular pain.
  • calcium channel blocking agent or “compound having calcium channel blocking activity” or “calcium channel antagonist” is used to define compounds which are known to prevent or delay the cardiac contracture which is caused by an accumulation of intracellular calcium.
  • Suitable calcium channel blockers include verapamil, nifedipine, diltiazem, fostedil and the various derivatives, including the analogues and homologues, thereof, having calcium channel blocking activity.
  • Verapamil and the like are disclosed in U.S. Patents 3,261,859; 4,593,042 and 4,681,970.
  • Nifedipine is disclosed in U.S. Patent 3,485,847 and is a 1,4- dihydropyridine in which the 2 and 6 positions are substituted by methyl groups, the 4 position by 2-nitrophenyl and the 3 and 5 positions by carboxylic acid methyl ester groups. Similar compounds are disclosed in U.S. Patent Nos.
  • 4,307,103 and 4,393,070 to Sato disclose 1,4- dihydropyridines in which the 2 position is not substituted by alkyl, but instead is substituted with cyano, formyl or certain other substituents and the ester group in the 3 position may contain various substituted alkyl groups including substituted alkylaminoalkyl, heterocyclic aminoalkyl and aroylaminoalkyl, including phthalimidoethyl.
  • U.S. Patent No. 4,448,964 to Muto, et al. discloses compounds in which the 3-position ester group contains certain substituted piperidinyl alkylene groups.
  • Calcium channel blocking activity varies substantially from compound to compound. Generally, when administered systemically, calcium channel blocking agents are effective in a wide range of concentrations. For example, diltiazem tablets contain 30 to 120 mg of active ingredient per tablet.
  • calcium channel blocking agents may be administered in any manner which will deliver the drug directly to the locale of the pain to be treated. It is anticipated that this will be by application to the immediate area of distress.
  • the drug could be applied topically, or by subcutaneous injection or by some similar means which delivers the drug directly to the affected area. It is not intended that this invention be practiced by administering the drug in such a way as to insure that it gets to the central nervous system. In fact, that would defeat the whole purpose of this invention which is focused on treating the pain at its source.
  • solutions are prepared typically containing from about 0.001% to about 1.0% of active ingredient, and a physiological saline solution as a major vehicle.
  • the pH of such ophthalmic solutions should preferably be maintained between 6.5 and 7.2 with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and/or penetration enhancers.
  • the preferred vehicle that may be used in the ophthalmic solutions of the present invention is purified water, more preferably a physiological saline solution.
  • Additional suitable vehicles include but are not restricted to, viscosity agents such as polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, carbomer and hydroxyethyl cellulose.
  • Preferred preservatives that may be used in the ophthalmic formulations of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.
  • Penetration enhancers may, for example, be surface active agents; certain organic solvents, such as dimethylsulfoxide and other sulfoxides, dimethylacetamide and pyrrolidone; certain amides of heterocyclic amines, glycols (e.g., propylene glycol); propylene carbonate; oleic acid; alkyl amines and derivatives; various cationic, anionic, nonionic, and amphoteric surface active agents; and the like.
  • Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable opthalmically acceptable tonicity adjustor.
  • buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers for ophthalmic use.
  • an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
  • excipient components which may be included in the ophthalmic preparations are chelating agents.
  • the preferred chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • a clinical study is performed to compare the analgesic effect of topically administered diltiazem and placebo following radial keratotomy surgery.
  • One hundred and twenty-four male and female subjects, 21 to 45 years of age, who undergo routine, elective, unilateral radial keratotomy for the correction of myopia participated in the study, and diltiazem was administered as a 0.03% ophthalmic solution.
  • Each subject receives one drop of the assigned study medication every four hours while awake one day prior to s .gery and again every 20 minutes for the two hours just before surgery. Each subject then undergoes unilateral radial keratotomy. Following surgery, each subject receives one drop of the study medication in the operated eye every four hours while awake for 14 consecutive days. Postoperative examinations occur at days 1, 3, 7 and 14. Efficacy is assessed by evaluation of pain intensity, pain relief, subjective global analgesic efficacy. Symptoms of ocular inflam ation (burning/stinging, tearing, etc.) are also recorded.
  • EXAMPLE 2 A 54 year old woman, hard contact lens wearer, has a one day history of sharp shooting pain in both eyes. Diltiazem was prescribed as a sole treatment of pain. On instillation of the medication, the patient reports relief of pain for approximately two and a half hours. Upon recurrence of pain, a second dose of diltiazem provides pain relief.
  • EXAMPLE 3 A 32 year old female patient with a history of gas-permeable contact lens wear has a two-to-three day history of pain in her left eye. The patient is treated with diltiazem for pain. The patient reports relief of pain for two hours.
  • EXAMPLE 4 An experiment was carried out in adult cats anaesthetized with sodium pantobarbitone 'Nembutal, 40mg/kg, I.P.). In order to keep a deep arreflexic state during the experiment, a dilute solution of the anaesthetic (15mg/ml) was infused through the radial vein. The animal was secured to a stereotaxic frame, tracheotomized and left to breathe spontaneously. End-tidal CO2 was continuously monitored to remain around 4%. Rectal temperature was maintained between 36-38 ⁇ C with a heating blanket. The superior and lateral walls of the orbital cavity were removed and the extrinsic muscles of the eye resected to expose the ciliary nerves.
  • a ciliary nerve was carefully dissected under a binocular microscope and placed on Ag-AgCl electrodes.
  • Conventional electrophysiological equipment consisting of a.c. amplifier with modifiable filters, oscilloscope and loudspeaker, was used to record impulse discharges.
  • Conduction velocities were calculated from the delay of the evoked response to suprathreshold electric shocks (0.1-0.5 ms, 0.5-3 mA), applied with a pair of polished silver electrodes on the limbus or the cornea.
  • Mechanical stimulation was performed manually, using a wet, fine brush. To measure mechanical threshold, a calibrated Cochet-Bonnet esthesiometer was employed.
  • the receptive field was mapped using the tip of the esthesiometer adjusted at suprathreshold values [Belmonte and Giraldez, J. Phvsiol. 321, 355 (1981)]. Chemical substances were assayed by applying with a pipette on the receptive field 60 microliters of the test solution for 60 s. After treatment, the area was washed repeatedly with balanced saline. Concentrations of chemicals used were as follows: Acetic acid, 10 mmol.l' 1 dissolved in distilled water, citric acid. Impulse discharges were stored on an FM tape for later off-line computer analysis.
  • Figure 1 also illustrates the influence of increased (Ca 2+ ) 0 .
  • a reduction of the amplitude of the firing response to a pH 4.5 citric acid solution was obtained after exposure of the cornea to 40 mM Ca 2+ whereas mechanical sensitivity remained unaltered. The effect was reversible after washing of the cornea for 5 min with the control solution.
  • Increases in (H + ) 0 occur during tissue injury and hypoxia and may contribute to stimulation and/or sensitization of nociceptors and thus to pain.
  • the fact that responses of a single fiber to acid could be blocked pharmacologically with Ca 2+ antagonists without interfering with mechanical responsiveness opens therapeutical possibilities in the management of pain of peripheral origin.
  • EXAMPLE 5 This experiment was carried out in adult cats. Nerve activity was recorded either from nerve filaments containing several corneal sensory fibers or from single corneal afferent units identified as polymodal nociceptors. Corneal receptive fields innervated by active fibers were stimulated mechanically with a Cochet-Bonnet esthesiometer and chemically with lOmM acetic acid. Verapamil (1 mM) or nifedipine (1 mM) were applied topically 5 min later. Mechanical and chemical stimulation were repeated twice with 5 min intervals; then, the cornea was washed for 30 min and sensitivity to acid and to mechanical stimulation again tested. Number of impulses during 60s following application of acid was counted. The effect of drugs was expressed as percent reduction of the control response to acid.
  • Verapamil assayed in three single units produced in two of them an increase in ongoing firing frequency (from 0.01 to 0.10 and from 0.04 to 0.15) and no changes in the remaining unit. It reduced in all fibers the response to acid to an average value of 19.7% of control. Mechanical threshold increased in two of the units and remained unaltered in the third. A reduction of size of the receptive field was noticed in all instances after verapamil.
  • Nifedipine was tested in three filaments displaying multiunit discharges; in one of them, application of nifedipine produced a clear increase of ongoing activity; the other two responded to the administration of the drug either with a small and short-lasting frequency increase or with no change in spontaneous activity. Discharges evoked by subsequent applications of acid were markedly reduced by nifedipine in the three filaments explored, to an average value of 15% of control. Responses to mechanical stimulation persisted after nifedipine. Nevertheless, the presence of many different units in the recording precluded a determination of threshold; also, the possibility that a portion of the fibers were inactivated by the drug cannot be excluded in these experimental conditions.
  • nifedipine and verapamil reduce chemical responsiveness of nociceptors as occurs with diltiazem.
  • both drugs at the doses employed, show a brief discharge of impulses upon instillation.
  • a certain degree of inactivation of mechanical responsiveness was observed with verapamil.
  • This experiment is directed to demonstrate that calcium blockers reduce ocular pain and inflammatory reactions in rabbits.
  • Two types of experiments are done: Group 1 In a first group of experiments, forty-one (41) adult albino rabbits are employed. Animals received in both eyes 60 ⁇ l of 1% capsaicin (8.5% Tween 80, 1.5% ethanol in isotonic saline) with a 5 min interval between eyes.
  • Topical capsaicin produced an immediate motor response composed by scratching movements with the forepaw (wipes) directed to the eye; the animal closed totally or partially the eye (blepharospasm) and maintained afterwards a certain degree of palpebral closure. Miosis and conjunctival hyperemia were also present. These phenomena lasted for about 1-1.5 h.
  • Statistical comparisons (paired t-test) were made between the eye that was pre-treated with diltiazem and the contralateral, vehicle-treated eyes. Significant differences in motor responses (number of wiping movements, blepharospasm and palpebral opening) were noticed at the three doses tested.
  • Miosis tends to be less marked in the eye treated with diltiazem than in contralateral eyes but differences are conclusive.
  • Conjunctival hyperemia is reduced significantly by diltiazem.
  • the subjective evaluation of discomfort also shows a significantly reduced value in eyes treated with diltiazem.
  • Significant differences in fiuorescein or protein content in aqueous humor were noticed between diltiazem-treated and control eyes.
  • Ultraviolet radiation produced an inflammatory reaction of the anterior uvea that was not detectable at 8 hours but was clearly apparent 24 hours after exposure. In preliminary experiments we had detected that the inflammatory effect of UV radiation was more prominent in pigmented rabbits; for this reason that species was selected for this study.
  • the method of the present invention may be used to treat pain in other parts of the body than the eye. Moreover, certain pain will require systemic rather than topical administration and, therefore, treating pain systemically is within the scope of the present invention.
  • polymodal nociceptors of the eye i.e., the class of nociceptive nerve terminals that respond to lesive mechanical, thermal and chemical stimuli are analogous to those found in the skin and mucosae or in the teeth, (this is not surprising, considering that these tissues share a common embryological origin).
  • this invention can be extended to the local treatment of superficial pain and neurogenic inflammation of the skin and mucosae.

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Abstract

On utilise un inhibiteur calcique pour fabriquer un médicament destiné à soulager la douleur, par exemple la douleur oculaire. Parmi les inhibiteurs calciques que l'on peut utiliser à cette fin, on trouve le diltiazem, le vérapamil, la nifédipine, la nicardipine et la nimodipoïne.
PCT/EP1991/001656 1990-09-07 1991-08-30 Composition pour le traitement des douleurs oculaires WO1992004008A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP91513914A JPH05506035A (ja) 1990-09-07 1991-08-30 眼痛治療用組成物
AU83971/91A AU644679B2 (en) 1990-09-07 1991-08-30 Composition for treating ocular pain
EP91915701A EP0502143B1 (fr) 1990-09-07 1991-08-30 Composition pour le traitement des douleurs oculaires
DE69114470T DE69114470T2 (de) 1990-09-07 1991-08-30 Komposition für die behandlung von augenschmerzen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES9002335 1990-09-07
ES9002335 1990-09-07

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WO1992004008A1 true WO1992004008A1 (fr) 1992-03-19

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EP (1) EP0502143B1 (fr)
JP (1) JPH05506035A (fr)
AT (1) ATE129890T1 (fr)
CA (1) CA2073003A1 (fr)
DE (1) DE69114470T2 (fr)
IE (1) IE913137A1 (fr)
PT (1) PT98895A (fr)
WO (1) WO1992004008A1 (fr)

Cited By (14)

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WO1995007080A1 (fr) * 1993-09-08 1995-03-16 Mclean, William, Alexander Methode de traitement de maladie hepatique et d'indications analogues au moyen d'agents vasodilatateurs
WO1995034299A1 (fr) * 1994-06-10 1995-12-21 Telor Ophthalmic Pharmaceuticals, Inc. Inhibition du myosis/de la production de mydriase peroperatoire par des agents bloquant les canaux calciques
WO1997021445A1 (fr) * 1995-12-12 1997-06-19 Omeros Medical Systems, Inc. Solution d'irrigation vasculaire et methode d'inhibition de la douleur, de l'inflammation, du spasme et de la restenose
WO1997038693A1 (fr) * 1996-04-18 1997-10-23 Alcon Laboratories, Inc. Antagonistes du calcium utilises comme inhibiteurs de la degranulation du mastocyte conjonctival chez l'homme pour le traitement d'allergies oculaires
WO1997048396A1 (fr) * 1996-06-20 1997-12-24 Pharmacy & Therapeutic Advisory Consultancy Ltd. Procede de traitement de maladies du foie et d'etats similaires a l'aide d'agents vasodilatateurs
US5800385A (en) * 1994-12-12 1998-09-01 Omeros Medical Systems, Inc. Vascular irrigation solution and method for inhibition of pain, inflammation, spasm and restenosis
US5820583A (en) * 1995-12-12 1998-10-13 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US6174917B1 (en) 1993-09-08 2001-01-16 Pharmacy And Therapeutic Advisory Consultancy Ltd. Method of treating liver disease and like indications with vasodilating agents
US6413961B1 (en) 1995-12-12 2002-07-02 Omeros Medical Systems, Inc. Irrigation solution and method for inhibition of pain and inflammation
US6492332B1 (en) 1995-12-12 2002-12-10 Omeros Corporation Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
US8173707B2 (en) 2002-07-30 2012-05-08 Omeros Corporation Ophthalmologic irrigation solutions and method
US9066856B2 (en) 2012-10-24 2015-06-30 Omeros Corporation Stable preservative-free mydriatic and anti-inflammatory solutions for injection
US11234965B2 (en) 2014-12-01 2022-02-01 Omeros Corporation Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions

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US6294553B1 (en) * 2000-02-15 2001-09-25 Allergan Sales, Inc. Method for treating ocular pain
WO2004069275A1 (fr) * 2003-02-04 2004-08-19 Mitsubishi Pharma Corporation Medicaments ophtalmiques
RU2015138686A (ru) * 2013-02-13 2017-03-17 Новартис Аг Анальгетические средства для местного офтальмологического применения

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US4981871A (en) * 1987-05-15 1991-01-01 Abelson Mark B Treatment of ocular hypertension with class I calcium channel blocking agents

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US4981871A (en) * 1987-05-15 1991-01-01 Abelson Mark B Treatment of ocular hypertension with class I calcium channel blocking agents
WO1990006123A1 (fr) * 1988-12-05 1990-06-14 Houston Biotechnology Incorporated Utilisation therapeutique d'agents bloquant l'entree de calcium dans le dysfonctionnement du nerf retinie ou optique

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Title
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THE LANCET, 1981, J. WALTON, "Diffuse Exercise-Induced Muscle Pain of Undertermined Cause Relieved by Verapamil", page 993. *

Cited By (33)

* Cited by examiner, † Cited by third party
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WO1995007080A1 (fr) * 1993-09-08 1995-03-16 Mclean, William, Alexander Methode de traitement de maladie hepatique et d'indications analogues au moyen d'agents vasodilatateurs
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PT98895A (pt) 1992-07-31
ATE129890T1 (de) 1995-11-15
CA2073003A1 (fr) 1992-03-08
EP0502143B1 (fr) 1995-11-08
JPH05506035A (ja) 1993-09-02
EP0502143A1 (fr) 1992-09-09
IE913137A1 (en) 1992-03-11
DE69114470D1 (de) 1995-12-14
DE69114470T2 (de) 1996-07-18

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